Oral Immunotherapy with IgA to Treat C. difficile Infection

摘要 艰难梭菌感染，与疟疾相关的原因 伪膜性结肠炎是一个日益严重的全国性健康问题。发生率 初级C。美国住院患者中的难治性感染> 30万 案件每年。复发率很高。由于这些原因， 迫切需要新的基于非抗生素的治疗方法来治疗这种疾病， 可能危及生命的疾病。提出的新治疗方法， 本申请是一种口服免疫疗法， 通过创新技术形成的人单体和分泌型伊加（sIgA） 将血浆衍生的二聚体伊加与重组人IgA结合的方法 分泌成分这种创新的免疫疗法将提供一个重要的 与胃肠外给药的被动免疫相比的临床优势 重组单克隆和多克隆IgG抗体。原则证明是 确立了习我们已经证明，血浆来源的sIgA提供了一种免疫调节剂， 对感染C.很难治疗， 亚治疗剂量万古霉素其他人发现血浆来源的sIgA 能有效预防C.艰难梭菌病小鼠模型。的 该项目的长期目标是将口服给药商业化， 半合成人分泌型免疫球蛋白A用于治疗C.艰难 感染具体目的是：1）确定口服的最小剂量 给予伊加和sIgA，这是一种有效的预防性治疗， 仓鼠模型艰难病2)确定是否口服给药 人伊加混合物在2周小鼠毒性模型中导致任何毒性。 3)评估用sIgA治疗前后小鼠的肠道微生物组。 4)确定口服伊加和sIgA是否有效， 治疗开始于C.艰难梭菌孢子挑战。5.稳定性评价 血浆来源的伊加和sIgA。6：确定是否有 口服施用的人伊加的全身吸收。7.确立GLP水平 产品批次纯度和鉴别的标准操作规程（SOP）。 和8）将生产方法转移到Emergent BioSolutions， 开发和制造组织（CDMO）的规模扩大。

Abstract Clostridioides difficile infection, the cause of antibiotic-associated pseudomembraneous colitis, is a growing national health problem. The incidence of primary C. difficile-infection in the hospitalized U.S. population is >300,000 cases annually. There is a high incidence of relapse. For these reasons there is an urgent need for new non-antibiotic based therapeutic approaches to treat this potentially life threatening disease. The novel therapeutic approach proposed in this application is an orally administered immunotherapy consisting of polyclonal human monomeric and secretory IgA (sIgA) formed by the innovative technical process of combining plasma derived dimeric IgA with recombinant human secretory component. This innovative immunotherapy will provide a significant clinical advantage over passive immunization with parenterally administered recombinant monoclonal and polyclonal IgG antibodies. Proof of Principle is established. We have demonstrated that plasma derived sIgA provides a survival advantage to hamsters infected with C. difficile and treated with a subtherapeutic dose of vancomycin. Others have found that plasma derived sIgA was effective in preventing relapse of C. difficile disease in a mouse model. The long-term goal of this project is to commercialize orally administered semisynthetic human secretory immunoglobulin A for the treatment of C. difficile infection. The Specific Aims are: 1) Determine the minimal dose of orally administered IgA and sIgA that is an effective prophylactic treatment in the hamster model of C. difficile disease. 2) Determine whether orally administered human IgA- sIgA mixture results in any toxicity in a 2 week mouse toxicity model. 3) Assess the intestinal microbiome of mice before and after treatment with sIgA. 4) Determine whether orally administered IgA and sIgA is effective when treatment begins after the C. difficile spore challenge. 5. Evaluate the stability of plasma derived IgA and sIgA during storage. 6: Determine whether there is systemic absorption of orally administered human IgA. 7. Establish GLP level Standard Operating Procedures (SOP) for purity and identity of product batches. and 8) Transfer production methods to Emergent BioSolutions, a contract development and manufacturing organization (CDMO) for scale-up.